Environmental fluctuations in the human oral cavity favor an increase in the amount of cariogenic bacteria, including Streptococcus mutans the etiological agent of dental caries. Dental caries is the most common chronic disease in children, can greatly impact quality of life, and represents 5-10% of healthcare expenditures in industrialized nations. The virulence of S. mutans resides in three core attributes: its ability to form biofilms on the tooth surface, to produce large quantities of organic acids from a wide range of carbohydrates, and its ability to tolerate environmental stressors. Of interest, a very strong correlation exists between stress tolerance, biofilm formation and natural genetic competence [or the ability to uptake external DNA from the environment]. Greater understanding of how these processes are connected and how they benefit the organism is needed. This study investigates a primary stress response pathway and its affects on competence development. Preliminary data indicates that a deletion of the (p)ppGpp synthetase/hydrolase enzyme RelA significantly reduces the organism's response to the competence stimulating peptide XIP, leading to deficiencies in transformation frequency. The proposed investigation will determine the mechanism by which competence induction is diminished through loss of the RelA enzyme, as well as the role of the enzyme in unimodal/bimodal switching of alternative sigma factor comX expression. Also, the rcrRPQ operon was recently found to modulate the expression of a novel protein termed ComX2 encoded entirely within the comX gene. Further description of this protein on cell physiology is needed as it serves as a potential target for therapeutic intervention. Two aims are proposed: 1) Examine the role of, and mechanisms by which, the bi-functional (p)ppGpp synthetase/hydrolase enzyme RelA modulates virulence and competence gene expression and 2) Further characterize the novel protein ComX2 and its role in competence development. This research supports the NIDCR goal to investigate cariogenic organisms to identify genes and pathways that contribute to the decay process. Additionally this research represents the basis of a doctoral dissertation project. Hence, this fellowship application will assist in training a studet with an interest in oral health research to become an independent investigator.